Aurora B is a kinase that plays a role in cell division. Kinases are proteins that add phosphate groups to other proteins, activating or deactivating them. This enzyme orchestrates the precise steps required for a cell to accurately duplicate itself. Without it, cell division can falter, leading to errors in the genetic material passed on to new cells.
The Essential Role of Aurora B in Cell Division
Aurora B performs its functions as part of a larger assembly called the Chromosomal Passenger Complex (CPC). This complex localizes to the centromeres, constricted regions on chromosomes where spindle microtubules attach. The CPC ensures that chromosomes are properly aligned and segregated evenly into daughter cells.
Aurora B oversees correct chromosome attachment to the mitotic spindle. During cell division, chromosomes must connect to spindle microtubules from opposite poles, a configuration known as bi-orientation. Aurora B senses the tension generated by these correct attachments. If an attachment is incorrect, such as when both sides of a chromosome attach to the same spindle pole, there is insufficient tension.
In response to this lack of tension, Aurora B phosphorylates specific proteins at the kinetochore, the protein structure on the chromosome where microtubules bind. This phosphorylation weakens the connection between the kinetochore and the microtubule, allowing the incorrect attachment to detach. This allows the cell to form a proper, tension-generating connection, preventing an uneven distribution of chromosomes. This error-correction mechanism is supervised by the spindle assembly checkpoint, which Aurora B helps regulate.
Aurora B also orchestrates cytokinesis, the final stage of cell division where the cell divides into two daughter cells. After chromosomes have separated and moved to opposite poles, Aurora B relocates from the centromeres to the central spindle microtubules and eventually concentrates at the midbody. This positions Aurora B at the cell’s equator, signaling where the contractile ring should form. The contractile ring then constricts, pinching the cell in two and completing the division process.
Regulating Aurora B Activity and Location
The cell employs precise mechanisms to control Aurora B, ensuring its activity is confined to specific times and locations during division. This tight regulation is necessary for accurate cell replication. The enzyme’s activation and deactivation, known as temporal regulation, are largely controlled through phosphorylation.
Aurora B is activated during mitosis when other enzymes add phosphate groups to it. This activation is also influenced by its binding to other components of the Chromosomal Passenger Complex, particularly INCENP. Conversely, dephosphorylation events can inactivate Aurora B when no longer needed.
The spatial regulation of Aurora B is also important, as its location changes throughout mitosis. In early mitosis, it associates with the inner centromeres of chromosomes. As the cell progresses into anaphase, Aurora B moves to the central spindle, a structure formed by overlapping microtubules. During telophase and cytokinesis, it becomes concentrated at the midbody, which marks the site of cell cleavage. This precise localization ensures Aurora B acts on its targets at appropriate times in the cell cycle.
Consequences of Aurora B Malfunction
When Aurora B malfunctions, the precision of cell division can be disrupted, leading to cellular errors. A direct consequence is the failure of proper chromosome segregation, resulting in daughter cells with an incorrect number of chromosomes. This condition is called aneuploidy, where cells possess too many or too few chromosomes.
Aneuploidy can have serious effects, contributing to developmental issues and being a feature of many cancers. Cells that divide with an abnormal chromosome count often struggle to function or may undergo programmed cell death. However, some aneuploid cells survive and continue to divide, passing on their genetic instability.
Many cancer cells exhibit elevated levels of Aurora B, which can lead to reduced phosphorylation of its target proteins and contribute to mitotic defects. This increased Aurora B expression can cause chaotic cell division, including misaligned chromosomes, lagging chromosomes, and multipolar spindles. Such genomic instability, characterized by widespread changes in chromosome number and structure, is a hallmark of cancer and can drive tumor formation and progression. Overexpression of Aurora B has also been linked to a reduced DNA damage response and decreased levels of the cell cycle inhibitor p21Cip1, contributing to uncontrolled cell growth and tumor development.
Targeting Aurora B in Cancer Therapy
Because Aurora B is often overactive or dysregulated in cancers, it has become a target for anti-cancer drugs. Researchers have developed compounds known as Aurora B inhibitors to block its activity. The goal of these inhibitors is to disrupt the abnormal cell division characteristic of cancer cells, thereby halting tumor growth.
These drugs primarily work by preventing Aurora B from phosphorylating its target proteins, which are necessary for correct chromosome segregation and cytokinesis. By interfering with these processes, Aurora B inhibitors can cause cancer cells to arrest in mitosis, preventing them from dividing further. This mitotic arrest can ultimately lead to programmed cell death in the rapidly proliferating cancer cells, while having less impact on normal, slower-dividing cells.
The development of Aurora B inhibitors is an active area of research, with several compounds having advanced into clinical trials. While some early inhibitors faced challenges with efficacy and toxicity, newer generations aim for greater specificity to improve therapeutic potential and reduce side effects. These ongoing trials are exploring the use of Aurora B inhibitors in various malignancies, including acute myeloid leukemia, diffuse B-cell lymphoma, and advanced solid tumors. The continued investigation of these inhibitors highlights the potential for biological discoveries to translate into new strategies for cancer treatment.